This research project is designed to investigate cellular signaling pathways in the limbic forebrain that are impacted by stress and contribute to the pathophysiology of depression. The mechanism of action of antidepressant medications will also be investigated, with specific regard to the subcellular processes responsible for their clinical efficacy. I will test whether activity of the nonreceptor tyrosine kinase Pyk2 in the lateral septum is involved in these processes. Using gel electrophoresis and immunoblotting techniques, protein levels from the lateral septum will be measured in rats administered stress and antidepressant drugs to see if such treatments alter Pyk2 activity. Viral-mediated gene transfer will also be used to directly manipulate the levels of Pyk2 activity in the lateral septum and the effects such treatment has in animal models of depression will be evaluated. It is hypothesized that stress precipitates depressive symptoms by diminishing Pyk2 activity in the lateral septum, while the clinical efficacy of antidepressant drugs follows from enhanced activity. These experiments should provide new and useful information regarding the neural and cellular pathways that contribute to depression in humans.